Chronic gingival inflammation afflicts over half of all American adults and can progress to periodontal disease, eventually resulting in tooth loss. Periodontitis is initiated by bacterial infection of the gingival tissues through a subgingival microbial biofilm on the tooth surface that releases bacterial lipopolysaccharide (LPS) and other antigens. In turn, LPS induces leukocyte and monocyte-mediated inflammation that causes gingival tissue destruction and alveolar bone resorption. The gingival crevice deepens into a periodontal pocket, the periodontal ligament is destroyed, and the involved tooth loses attachment. Notably, periodontal infection and inflammation can substantially increase the risk of systemic conditions, including cardiovascular and renal diseases, and pregnancy complications. Periodontal disease is exacerbated in diabetics and smokers due to increased exposure to advanced glycation end-products (AGEs), which arise from spontaneous glycation of proteins. AGEs from high blood sugar or from inhalation of AGES from tobacco products amplify inflammation by ligation of the cell-surface receptor for AGEs, or RAGE. Recently, RAGE-mediated inflammation has been implicated in periodontal inflammation and osteoclastogenic bone loss. Since blockade of RAGE inhibits periodontitis-associated alveolar bone loss in diabetic animals, RAGE is an attractive target for intervention in periodontal disease. Sulfated glycosaminoglycans (GAGs, e.g., heparin) block ligation of RAGE by AGE and its other ligands. GAGs show other activities that could also be beneficial in treating gingivitis, including prevention of gram-negative bacteria attachment, disruption of gram negative microbial biofilm formation, inhibition of cytokine secretion by LPS-stimulated monocytes, and inhibition of matrix metalloproteinase (MMP) production by interleukin-12 (IL-12)-stimulated gingival fibroblasts. GlycoMira is developing semi-synthetic glycosaminoglycan ethers (SAGEs) as safe and effective inflammation-modulating inhibitors of RAGE. Specifically, in this Phase I SBIR project, we will establish the feasibility of using SAGEs as a novel therapy for gingivitis and periodontitis in two Specific Aims. First, we will test the ability of SAGEs to inhibit inflammatory events relevant to periodontal diseases in vitro, including biofilm formation by Porphyromonas gingivalis, cytokine production by LPS- or AGE-stimulated human monocyte/macrophages, matrix metalloproteinase production by IL-12-stimulated human gingival fibroblasts, and AGE-induced inhibition of extracellular matrix production by gingival fibroblasts. Second, we will test the therapeutic potential of SAGEs in vivo using a model of accelerated periodontal inflammation and alveolar bone loss, the P. gingivalis-infected, streptozotocin-induced diabetic rat. GlycoMira works with a world-class team of practicing periodontists on experimental models for preclinical data collection, with the goal of filing an Investigational New Drug Application (IND) as a milestone for the Phase II project. PUBLIC HEALTH RELEVANCE: Chronic gingival inflammation afflicts over half of all American adults, evolves into frank periodontal disease, and results in tooth loss. Periodontitis is caused by infection of the gingival crevice and production of subgingival microbial plaque, which results in leukocyte-mediated inflammation and alveolar bone resorption. Importantly, periodontal disease is exacerbated by diabetes and smoking, and periodontitis substantially increases the risk of systemic illness such as cardiovascular and renal disease, rheumatoid arthritis, and pregnancy complications. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as a simple mechanistically-based treatment for this chronic extraordinarily common dental disorder.